tbuckley/cabot-search huggingface dataset:
A novel fixed-combination timolol-netarsudil-latanoprost ophthalmic solution for the treatment of glaucoma and ocular hypertension
Authors: Tao Wang, Yunran Zhang, Meiling Chi, Chen Zhao, Linlin Cao, Chutong Tian, K. Kamei, Ying Zheng, Qikun Jiang
Journal: Asian Journal of Pharmaceutical Sciences (2022)

Currently commercial fixed-concomitant three agents have multiple problems such as multiple dosing administration, poor efficacy and side effects. Once-daily fixed-combination timolol-netarsudil-latanoprost ophthalmic solution (FC-TNL) has the ability to treat glaucoma by lowering the intraocular pressure (IOP) with great efficacy and improving patient compliance. However, the commercialized netarsudil dimesylate precipitated when the pH of the solution was above 5.4, or when maleic acid, the salt of commercial timolol maleate, was mixed with netarsudil dimesylate. Consequently, the homologous salt engineering strategy was used to make netarsudil dimesylate soluble in pH 4.8-5.2 solution by synthesizing timolol mesylate. Next, the morphology of timolol mesylate was observed by scanning electron microscopy, differential scanning calorimetry, thermogravimetric analysis, and powder X-ray diffraction. The prepared FC-TNL showed good stability during refrigeration storage. Additionally, FC-TNL exerted no influence on the intraocular penetration of each active compounds in the pharmacokinetic study. Importantly, once-daily FC-TNL exerted potent IOP-lowering effect and protective effect on retinal ganglion cells. The FC-TNL was stable, safe and effective, being a promising glaucoma therapeutic.
Liposomes and liposome-like nanoparticles: From anti-fungal infection to the COVID-19 pandemic treatment
Authors: Yonglong He, Wanting Zhang, Qingqing Xiao, Lifang Fan, Dechun Huang, Wei Chen, Wei He
Journal: Asian Journal of Pharmaceutical Sciences (2022)

The liposome is the first nanomedicine transformed into the market and applied to human patients. Since then, such phospholipid bilayer vesicles have undergone technological advancements in delivering small molecular-weight compounds and biological drugs. Numerous investigations about liposome uses were conducted in different treatment fields, including anti-tumor, anti-fungal, anti-bacterial, and clinical analgesia, owing to liposome's ability to reduce drug cytotoxicity and improve the therapeutic efficacy and combinatorial delivery. In particular, two liposomal vaccines were approved in 2021 to combat COVID-19. Herein, the clinically used liposomes are reviewed by introducing various liposomal preparations in detail that are currently proceeding in the clinic or on the market. Finally, we discuss the challenges of developing liposomes and cutting-edge liposomal delivery for biological drugs and combination therapy.
Genomic, transcriptomic, and epigenomic analysis of a medicinal snake, Bungarus multicinctus, to provides insights into the origin of Elapidae neurotoxins
Authors: Jiang Xu, Shuai Guo, Xianmei Yin, Mingqian Li, He Su, Xuejiao Liao, Qiushi Li, Liang Le, Shiyu Chen, Baosheng Liao, Haoyu Hu, Juan Lei, Yingjie Zhu, Xiaohui Qiu, Lu Luo, Jun Chen, Ruiyang Cheng, Zhenzhan Chang, Han Zhang, Nicholas Chieh Wu, Yiming Guo, Dianyun Hou, Jin Pei, Jihai Gao, Yan Hua, Zhihai Huang, Shilin Chen
Journal: Acta Pharmaceutica Sinica B (2022)

The many-banded krait, Bungarus multicinctus, has been recorded as the animal resource of JinQianBaiHuaShe in the Chinese Pharmacopoeia. Characterization of its venoms classified chief phyla of modern animal neurotoxins. However, the evolutionary origin and diversification of its neurotoxins as well as biosynthesis of its active compounds remain largely unknown due to the lack of its high-quality genome. Here, we present the 1.58 Gbp genome of B. multicinctus assembled into 18 chromosomes with contig/scaffold N50 of 7.53 Mbp/149.8 Mbp. Major bungarotoxin-coding genes were clustered within genome by family and found to be associated with ancient local duplications. The truncation of glycosylphosphatidylinositol anchor in the 3'-terminal of a LY6E paralog released modern three-finger toxins (3FTxs) from membrane tethering before the Colubroidea divergence. Subsequent expansion and mutations diversified and recruited these 3FTxs. After the cobra/krait divergence, the modern unit-B of β-bungarotoxin emerged with an extra cysteine residue. A subsequent point substitution in unit-A enabled the β-bungarotoxin covalent linkage. The B. multicinctus gene expression, chromatin topological organization, and histone modification characteristics were featured by transcriptome, proteome, chromatin conformation capture sequencing, and ChIP-seq. The results highlighted that venom production was under a sophisticated regulation. Our findings provide new insights into snake neurotoxin research, meanwhile will facilitate antivenom development, toxin-driven drug discovery and the quality control of JinQianBaiHuaShe.
Recent advances in diverse nanosystems for nitric oxide delivery in cancer therapy
Authors: Dan Gao, Sajid Asghar, Rongfeng Hu, Su Chen, Ruixin Niu, Jia Liu, Zhipeng Chen, Yanyu Xiao
Journal: Acta Pharmaceutica Sinica B (2022)

Gas therapy has been proven to be a promising and advantageous treatment option for cancers. Studies have shown that nitric oxide (NO) is one of the smallest structurally significant gas molecules with great potential to suppress cancer. However, there is controversy and concern about its use as it exhibits the opposite physiological effects based on its levels in the tumor. Therefore, the anti-cancer mechanism of NO is the key to cancer treatment, and rationally designed NO delivery systems are crucial to the success of NO biomedical applications. This review summarizes the endogenous production of NO, its physiological mechanisms of action, the application of NO in cancer treatment, and nano-delivery systems for delivering NO donors. Moreover, it briefly reviews challenges in delivering NO from different nanoparticles and the issues associated with its combination treatment strategies. The advantages and challenges of various NO delivery platforms are recapitulated for possible transformation into clinical applications.
Overall Survival With Daratumumab, Bortezomib, and Dexamethasone in Previously Treated Multiple Myeloma (CASTOR): A Randomized, Open-Label, Phase III Trial
Authors: Pieter Sonneveld, Asher Chanan-Khan, Katja Weisel, Ajay K. Nooka, Tamas Masszi, Meral Beksac, Ivan Spicka, Vania Hungria, Markus Munder, Maria-Victoria Mateos, Tomer M. Mark, Mark-David Levin, Tahamtan Ahmadi, Xiang Qin, Wendy Garvin Mayo, Xue Gai, Jodi Carey, Robin Carson, Andrew Spencer
Journal: Journal of Clinical Oncology (2022)

At the primary analysis of CASTOR (median follow-up, 7.4 months), daratumumab plus bortezomib and dexamethasone (D-Vd) significantly prolonged progression-free survival versus bortezomib and dexamethasone (Vd) alone in relapsed or refractory multiple myeloma (RRMM). We report updated efficacy and safety results at the final analysis for overall survival (OS).CASTOR was a multicenter, randomized, open-label, phase III study during which eligible patients with ≥ 1 line of prior therapy were randomly assigned to Vd (up to eight cycles) with or without daratumumab (until disease progression). After positive primary analysis and protocol amendment, patients receiving Vd were offered daratumumab monotherapy after disease progression.At a median (range) follow-up of 72.6 months (0.0-79.8), significant OS benefit was observed with D-Vd (hazard ratio, 0.74; 95% CI, 0.59 to 0.92; P = .0075). Median OS was 49.6 months with D-Vd versus 38.5 months with Vd. Prespecified subgroup analyses demonstrated an OS advantage with D-Vd versus Vd for most subgroups, including patients age ≥ 65 years and patients with one or two prior lines of therapy, International Staging System stage III disease, high-risk cytogenetic abnormalities, and prior bortezomib treatment. The most common (≥ 10%) grade 3/4 treatment-emergent adverse events with D-Vd versus Vd were thrombocytopenia (46.1% v 32.9%), anemia (16.0% v 16.0%), neutropenia (13.6% v 4.6%), lymphopenia (10.3% v 2.5%), and pneumonia (10.7% v 10.1%).D-Vd significantly prolonged OS in patients with RRMM, with the greatest OS benefit observed in patients with one prior line of therapy. To our knowledge, our results, together with the OS benefit observed with daratumumab plus lenalidomide and dexamethasone in the phase III POLLUX study, demonstrate for the first time an OS benefit with daratumumab-containing regimens in RRMM (ClinicalTrials.gov identifier: NCT02136134 [CASTOR]).
Is the Urokinase Plasminogen Activator/Plasminogen Activator Inhibitor-1 Ratio a Marker of Sonographic Septations in Pleural Infection?
Authors: Taro Yasuma, Corina N. D’Alessandro-Gabazza, Tetsu Kobayashi, Esteban C. Gabazza, Hajime Fujimoto
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

"Is the uPA/PAI-1 Ratio a Marker of Sonographic Septations in Pleural Infection?." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp. –
Return of non-ACMG recommended incidental genetic findings to pediatric patients: considerations and opportunities from experiences in genomic sequencing
Authors: Kevin M. Bowling, Michelle L. Thompson, Melissa A. Kelly, Sarah Scollon, Anne M. Slavotinek, Bradford C. Powell, Brian M. Kirmse, Laura G. Hendon, Kyle B. Brothers, Bruce R. Korf, Gregory M. Cooper, John M. Greally, Anna C. E. Hurst
Journal: Genome Medicine (2022)

Abstract Background The uptake of exome/genome sequencing has introduced unexpected testing results (incidental findings) that have become a major challenge for both testing laboratories and providers. While the American College of Medical Genetics and Genomics has outlined guidelines for laboratory management of clinically actionable secondary findings, debate remains as to whether incidental findings should be returned to patients, especially those representing pediatric populations. Methods The Sequencing Analysis and Diagnostic Yield working group in the Clinical Sequencing Evidence-Generating Research Consortium has collected a cohort of pediatric patients found to harbor a genomic sequencing-identified non-ACMG-recommended incidental finding. The incidental variants were not thought to be associated with the indication for testing and were disclosed to patients and families. Results In total, 23 "non-ACMG-recommended incidental findings were identified in 21 pediatric patients included in the study. These findings span four different research studies/laboratories and demonstrate differences in incidental finding return rate across study sites. We summarize specific cases to highlight core considerations that surround identification and return of incidental findings (uncertainty of disease onset, disease severity, age of onset, clinical actionability, and personal utility), and suggest that interpretation of incidental findings in pediatric patients can be difficult given evolving phenotypes. Furthermore, return of incidental findings can benefit patients and providers, but do present challenges. Conclusions While there may be considerable benefit to return of incidental genetic findings, these findings can be burdensome to providers and present risk to patients. It is important that laboratories conducting genomic testing establish internal guidelines in anticipation of detection. Moreover, cross-laboratory guidelines may aid in reducing the potential for policy heterogeneity across laboratories as it relates to incidental finding detection and return. However, future discussion is required to determine whether cohesive guidelines or policy statements are warranted.
From amputations to antibiotics: A future beyond “hacksaw” gene editing
Authors: Tristan Scott, Kevin V. Morris
Journal: Molecular Therapy (2022)

Nuclease-based gene editing could be likened to hacksaw surgery upon the genome. In fact, two recent papers have reiterated the untoward consequences of CRISPR-Cas-mediated double-stranded breaks (DSBs): p53-induced toxicity and effects upon the gross morphology of chromosomes. Álvarez et al. identified genomic sites of high p53 toxicity that appear more frequently observed at specific euchromatin markers and also noted variable levels of ploidy when targeting specific sites. 1 Álvarez M.M. Biayna J. Supek F. TP53-dependent toxicity of CRISPR/Cas9 cuts is differential across genomic loci and can confound genetic screening. Nat. Commun. 2022; 13: 4520 Crossref PubMed Scopus (9) Google Scholar Nahmad et al. report aneuploidy, the alteration of the chromosomal number, following CRISPR treatment at clinically relevant target sites in primary T cells. 2 Nahmad A.D. Reuveni E. Goldschmidt E. Tenne T. Liberman M. Horovitz-Fried M. Khosravi R. Kobo H. Reinstein E. Madi A. et al. Frequent aneuploidy in primary human T cells after CRISPR–Cas9 cleavage. Nat. Biotechnol. 2022; : 1-7 PubMed Google Scholar Taken together, these studies suggest a linkage between genome access, p53 toxicity, and aneuploidy. Notably, there were no sites free from p53 toxicity, just those with lower and higher levels of susceptibility.
E-cigarette exposure augments murine abdominal aortic aneurysm development: role of Chil1
Authors: Joscha Mulorz, Joshua M Spin, Pireyatharsheny Mulorz, Markus Udo Wagenhäuser, Alicia Deng, Karin Mattern, Yae H Rhee, Kensuke Toyama, Matti Adam, Hubert Schelzig, Lars Maegdefessel, Philip S Tsao
Journal: Cardiovascular Research (2022)

Abstract Aims Abdominal aortic aneurysm (AAA) is a common cardiovascular disease with a strong correlation to smoking, although underlying mechanisms have been minimally explored. Electronic cigarettes (e-cigs) have gained recent broad popularity and can deliver nicotine at comparable levels to tobacco cigarettes, but effects on AAA development are unknown. Methods and results We evaluated the impact of daily e-cig vaping with nicotine on AAA using two complementary murine models and found that exposure enhanced aneurysm development in both models and genders. E-cigs induced changes in key mediators of AAA development including cytokine chitinase-3-like protein 1 (CHI3L1/Chil1) and its targeting microRNA-24 (miR-24). We show that nicotine triggers inflammatory signalling and reactive oxygen species while modulating miR-24 and CHI3L1/Chil1 in vitro and that Chil1 is crucial to e-cig-augmented aneurysm formation using a knockout model. Conclusions In conclusion our work shows increased aneurysm formation along with augmented vascular inflammation in response to e-cig exposure with nicotine. Further, we identify Chil1 as a key mediator in this context. Our data raise concerns regarding the potentially harmful long-term effects of e-cig nicotine vaping.
cFLIP suppression and DR5 activation sensitize senescent cancer cells to senolysis
Authors: Liqin Wang, Haojie Jin, Fleur Jochems, Siying Wang, Cor Lieftink, Isabel Mora Martinez, Giulia De Conti, Finn Edwards, Rodrigo Leite de Oliveira, Arnout Schepers, Yangyang Zhou, Jiaojiao Zheng, Wei Wu, Xingling Zheng, Shengxian Yuan, Jing Ling, Kathy Jastrzebski, Matheus Dos Santos Dias, Ji-Ying Song, Patrick N. H. Celie, Hideo Yagita, Ming Yao, Weiping Zhou, Roderick L. Beijersbergen, Wenxin Qin, René Bernards
Journal: Nature Cancer (2022)
Where Microneedle Meets Biomarkers: Futuristic Application for Diagnosing and Monitoring Localized External Organ Diseases
Authors: Achmad Himawan, Lalitkumar K. Vora, Andi Dian Permana, Sumarheni Sudir, Airin R. Nurdin, Ririn Nislawati, Rafikah Hasyim, Christopher J. Scott, Ryan F. Donnelly
Journal: Advanced Healthcare Materials (2022)

Extracellular tissue fluids are interesting biomatrices that have recently attracted scientists' interest. Many significant biomarkers for localized external organ diseases have been isolated from this biofluid. In the diagnostic and disease monitoring context, measuring biochemical entities from the fluids surrounding the diseased tissues may give more important clinical value than measuring them at a systemic level. Despite all these facts, pushing tissue fluid-based diagnosis and monitoring forward to clinical settings faces one major problem: its accessibility. Most extracellular tissue fluid, such as interstitial fluid (ISF), is abundant but hard to collect, and the currently available technologies are invasive and expensive. This is where novel microneedle technology can help tackle this significant obstacle. The ability of microneedle technology to minimally invasively access tissue fluid-containing biomarkers will enable ISF and other tissue fluid utilization in the clinical diagnosis and monitoring of localized diseases. This review attempts to present the current pursuit of the application of microneedle systems as a diagnostic and monitoring platform, along with the recent progress of biomarker detection in diagnosing and monitoring localized external organ diseases. Then, the potential use of various microneedles in future clinical diagnostics and monitoring of localized diseases is discussed by presenting the currently studied cases.
What sounds like Aedes, acts like Aedes, but is not Aedes? Lessons from dengue virus control for the management of invasive Anopheles
Authors: Richard Allan, Sophie Budge, Hendrik Sauskojus
Journal: The Lancet Global Health (2022)

Aedes mosquitoes are responsible for transmission of dengue, chikungunya, Zika, and yellow fever viruses. Aedes mosquitoes are the pathfinders of invasive urban-living mosquitoes, and have spread into 129 countries over the past five decades. In the past 10 years Anopheles stephensi has been identified within densely populated cities in Yemen and across the Horn of Africa and as far west as Nigeria. A stephensi's aggressive spread is closely linked to increases in population movement due to migration, conflict, and climate change; rapid unplanned urbanisation; and resulting poor water quality, sanitation, waste container removal, and hygiene systems. As a highly invasive vector that is adept at transmitting malarial pathogens (eg, Plasmodium vivax and Plasmodium falciparum), A stephensi's spread holds huge implications for increasing malaria morbidity and mortality. Both vectors (ie, Aedes species and A stephensi) thrive in the same urban environments, and urgent action is needed to seize the opportunity to integrate disease control resources and generate innovative vector-control tools for urban populations, to protect the many millions at risk.
Unveiling the incidences and trends of the neglected zoonosis cystic echinococcosis in Europe: a systematic review from the MEmE project
Authors: Adriano Casulli, Bernadette Abela-Ridder, Daniele Petrone, Massimo Fabiani, Branko Bobić, David Carmena, Barbara Šoba, Enver Zerem, Maria João Gargaté, Gordana Kuzmanovska, Cristian Calomfirescu, Iskra Rainova, Smaragda Sotiraki, Vera Lungu, Balázs Dezsényi, Zaida Herrador, Jacek Karamon, Pavlo Maksimov, Antti Oksanen, Laurence Millon, Mario Sviben, Renata Shkjezi, Valbona Gjoni, Ilir Akshija, Urmas Saarma, Paul Torgerson, Viliam Šnábel, Daniela Antolová, Damir Muhovic, Hasan Besim, Fanny Chereau, Moncef Belhassen García, François Chappuis, Severin Gloor, Marcel Stoeckle, Beat Müllhaupt, Valerio Manno, Azzurra Santoro, Federica Santolamazza
Journal: The Lancet Infectious Diseases (2022)
Online mindfulness-based cognitive therapy for fatigue in patients with sarcoidosis (TIRED): a randomised controlled trial
Authors: Vivienne Kahlmann, Catharina C Moor, Sanne J van Helmondt, Rémy L M Mostard, Marije L van der Lee, Jan C Grutters, Marlies S Wijsenbeek, Marcel Veltkamp
Journal: The Lancet Respiratory Medicine (2022)
Recommendations for the development and use of imaging test sets to investigate the test performance of artificial intelligence in health screening
Authors: Anastasia Chalkidou, Farhad Shokraneh, Goda Kijauskaite, Sian Taylor-Phillips, Steve Halligan, Louise Wilkinson, Ben Glocker, Peter Garrett, Alastair K Denniston, Anne Mackie, Farah Seedat
Journal: The Lancet Digital Health (2022)
Development of a treatment selection algorithm for SGLT2 and DPP-4 inhibitor therapies in people with type 2 diabetes: a retrospective cohort study
Authors: John M Dennis, Katherine G Young, Andrew P McGovern, Bilal A Mateen, Sebastian J Vollmer, Michael D Simpson, William E Henley, Rury R Holman, Naveed Sattar, Ewan R Pearson, Andrew T Hattersley, Angus G Jones, Beverley M Shields
Journal: The Lancet Digital Health (2022)
An automated bedside measure for monitoring neonatal cortical activity: a supervised deep learning-based electroencephalogram classifier with external cohort validation
Authors: Saeed Montazeri, Manu Airaksinen, Päivi Nevalainen, Viviana Marchi, Lena Hellström-Westas, Nathan J Stevenson, Sampsa Vanhatalo
Journal: The Lancet Digital Health (2022)

BackgroundElectroencephalogram (EEG) monitoring is recommended as routine in newborn neurocritical care to facilitate early therapeutic decisions and outcome predictions. EEG's larger-scale implementation is, however, hindered by the shortage of expertise needed for the interpretation of spontaneous cortical activity, the EEG background. We developed an automated algorithm that transforms EEG recordings to quantified interpretations of EEG background and provides simple intuitive visualisations in patient monitors.MethodsIn this method-development and proof-of-concept study, we collected visually classified EEGs from infants recovering from birth asphyxia or stroke. We used unsupervised learning methods to explore latent EEG characteristics, which guided the supervised training of a deep learning-based classifier. We assessed the classifier performance using cross-validation and an external validation dataset. We constructed a novel measure of cortical function, brain state of the newborn (BSN), from the novel EEG background classifier and a previously published sleep-state classifier. We estimated clinical utility of the BSN by identification of two key items in newborn brain monitoring, the onset of continuous cortical activity and sleep-wake cycling, compared with the visual interpretation of the raw EEG signal and the amplitude-integrated (aEEG) trend.FindingsWe collected 2561 h of EEG from 39 infants (gestational age 35·0–42·1 weeks; postnatal age 0–7 days). The external validation dataset included 105 h of EEG from 31 full-term infants. The overall accuracy of the EEG background classifier was 92% in the whole cohort (95% CI 91–96; range 85–100 for individual infants). BSN trend values were closely related to the onset of continuous EEG activity or sleep-wake cycling, and BSN levels showed robust difference between aEEG categories. The temporal evolution of the BSN trends showed early diverging trajectories in infants with severely abnormal outcomes.InterpretationThe BSN trend can be implemented in bedside patient monitors as an EEG interpretation that is intuitive, transparent, and clinically explainable. A quantitative trend measure of brain function might harmonise practices across medical centres, enable wider use of brain monitoring in neurocritical care, and might facilitate clinical intervention trials.FundingEuropean Training Networks Funding Scheme, the Academy of Finland, Finnish Pediatric Foundation (Lastentautiensäätiö), Aivosäätiö, Sigrid Juselius Foundation, HUS Children's Hospital, HUS Diagnostic Center, National Health and Medical Research Council of Australia.
Lectin recruits pathogenic bugs
Authors: Charles R. Schutt, Sho Yamasaki
Journal: The Journal of Experimental Medicine (2022)

Colitis is an irritable bowel disorder affecting about 7 million patients worldwide, but the causes are diverse and not fully understood. In this issue, Matute et al. (2022. J. Exp. Med.https://doi.org/10.1084/jem.20211938) found that a stress-induced lectin, intelectin-1, recruits pathogenic bacteria to the gut and exacerbates colitis.